Eibl et al. (European Patent 225,608) describe the preparation and use of alkylphosphocholines for the treatment of tumors.
The starting material used in the Eibl process are the corresponding n-alcohol and phosphorus oxychloride. They are reacted in tetrahydrofuran to produce the phosphoric acid ester dichloride.
In a second step, 2-aminoethanol is reacted with the phosphoric acid ester dichloride to form the 2-hexadecyl-1,3,2-oxaphospholan-2-oxide in dioxane. Hydrolysis with 2N hydrochloric acid yields the open-chain amine which is exhaustively methylated to alkylphosphocholine with dimethyl sulphate in 2-propanol.
This process has the following disadvantages: it is necessary to isolate and purify the intermediate products. In addition, alkylating reagents are used. The use of potassium carbonate as an auxiliary base in this step of tie process leads to the product having a potassium content that is undesirably high for pharmaceutical purposes.
Long-chain alkylphosphocholines having an antimicrobial effect are described by Kanetani et al., Nippon Kayaku Kaushi, 9, 1452 (1984).
They are prepared using the following process: ethylene glycol and phosphorus trichloride are reacted to form 2-chloro-1,3,2-dioxaphospholane, the product is purified by distillation and is oxidized with oxygen to form 2-chloro-1,3,2-dioxaphospholane-2-oxide and then distilled again. The 2-chloro-1,3,2-dioxaphospholane-2-oxide is then reacted with 1-hexadecanol to 2-hexadecyl-1,3,2-dioxaphospholane-2-oxide. The 2-hexadecyl-1,3,2-dioxaphospholane-2-oxide is reacted with trimethylamine in an autoclave to hexadecylphosphocholine, the crude product is purified both with alkaline and with acid ion exchangers and then it is recrystallized from acetone/chloroform. The analogous process is also used to prepare the octyl-, decyl-, dodecyl, tetradecyl and octadecyl derivatives.
The disadvantage of this process is that it is necessary to work with increased pressure in the last step of the process and that the use of trimethyl amine constitutes an industrial hygiene problem. It is also a disadvantage that the hydrolysis-sensitive intermediate products 2-chloro-1,3,2-dioxaphospholane, 2-chloro-1,3,2-dioxaphospholane-2-oxide and 2-hexadecyl-2-oxa-1,3,2-dioxaphospholane need to be isolated and purified. In addition, environmentally-undesirable solvents such as benzene are used, the solvents being changed from step-to-step.
All known processes use chromatographic methods for working up and purifying the crude products. However, chromatographic working up processes of this kind have the following disadvantages:
their conversion to an industrial scale causes difficulties since the dimensions of the stationary phase cannot be increased at will, PA1 chromatographic processes are time-consuming.